WO97/44015 describes a dry powder fibrin sealant based on micro-particles of fibrinogen and thrombin. Further optimised formulations of these microparticle compositions is described in co-pending non-provisional application U.S. Ser. No. 12/636,718, herein incorporated by reference. In the Examples of this application, the components are prepared by spray-drying, fibrinogen with trehalose and thrombin with trehalose. Each product has a predominant particle size of up to 50 μm in diameter. The fibrin sealant, a blend of these components, has been demonstrated to be an easy-to-use, stable and efficacious topical hemostat. The product can be used immediately, without reconstitution. On contact with aqueous fluid such as blood, the exposed and/or dissolved active thrombin converts the exposed and/or dissolved fibrinogen into insoluble fibrin polymers.
New techniques, devices, and drugs for bleeding and bleeding and/or hemorrhage control are being developed. Despite all of the technology currently available, bleeding and hemorrhage control is still a major unresolved problem in emergency medical care. Almost 50% of all deaths in the first 48 hours of hospitalization are related to an inability to adequately control bleeding. Failure to stop bleeding within the first 24 hours is almost always fatal, especially when multiple trauma sites are involved.
It is generally accepted that hemostatic products for forward care in a battle zone must control bleeding quickly, be ready to use, simple to apply, have a shelf life approaching two years and prevent bacterial or viral transmission. The product's hemostatic action is time-critical in order to meet both military and civilian needs. Devices being investigated or used today as external methods of wound treatment range from absorbent pads containing clotting agents, pressure bandages, gauze, tourniquets for extremities, and trauma kits for wounds to the body.
Agents designed to stop external bleeding differ in composition and components are designed to help the rapid formation of a clot at the site of application. Clotting products generally contain high concentrations of materials such as human fibrinogen, thrombin, calcium, factor XIII and/or anti-fibrinolytics. In addition to fibrin, microporous polysaccharide macrobeads, mineral and synthetic zeolites, and chitosan (poly-N-acetyl glucosamine) are also available for use as hemostats. A number of new hemostatic products are available for treating wound trauma, for example, a bandage product using chitosan (deacetylated poly-N-acetyl glucosamine base, HemCon Inc., Tigard, Oreg.). However, it only has a shelf life of 18 months and its cost is prohibitive. Z-Medica Corporation, Wallingford, Conn., market a pressure bandage product (QuikClot) for use by U.S. troops. This product uses a granular, synthetic mineral zeolite to stop bleeding by adsorbing liquid and promoting clotting. However, QuikClot generates heat that can cause burns if the bandage isn't applied correctly.
ActSys Medical Inc., Westlake Village, Calif., provides a hemostatic gauze product, ActCel, which is a collagen-like natural substance created from chemically treated cellulose. It expands 3-4 times its original size when in contact with blood, thus sealing off damaged vessels and aiding clotting.
Medafor Inc., Minneapolis, Minn., sell a bio-inert, microporous polysaccharide macrobead product that is synthesized from potatoes, called TraumaDEX. This powdered microporous polymer product stops bleeding by expanding at the wound site and dehydrating the blood, whereupon the body absorbs the material within 48 hours.
Another non-bandage approach employs a non-zeolite topical powder containing a hydrophilic polymer and potassium salt (Quick Relief, Sarasota, Fla.) which, after application produces a flexible, protective scab to cover the wound site when the powder contacts the blood and slight pressure is applied.
No perfect solution currently exists for the treatment of excessive bleeding. Heat generation with respect to one type of agent is a major problem. The dressing's ability to adhere effectively when applied to deep wounds or wounds of irregular shape creates another major limitation. The ability to deal with excessive blood is another drawback, as is treatment and control of pressure bleeding from arterial bleeding.
Surgical and trauma wounds are the most common types of wounds addressed in the wound-care arena. Current bandages are made of gauze and are often applied in conjunction with an elastic bandage. They allow the wound to breath but are poor barriers to subsequent contamination. These bandages cannot stop serious bleeding and require the application of pressure in the case of arterial bleeding. Conventional wound sealants fail to present an optimized combination of speed of clotting, effectiveness under pressure bleeding conditions, and clots that are dynamic over time in response to the needs of the trauma site. Typical wound sealants are usually used in conjunction with separate wound dressings. Clearly, surgical trauma caused by sharp objects occurs in a clean environment. However, trauma wounds not caused in a controlled environment are often intermediate sized, widespread, and dirty wounds with considerable tissue damage are found in road traffic accidents or on the battlefield.
Abrasions are generally caused by scraping of the skin's outer layer; lacerations are jagged, irregular cuts or tears of the skin; punctures are caused by an object piercing the skin layers, creating a small hole; incisions are cuts commonly caused by knives or other sharp objects; and burns cause damage which may vary greatly in depth, size, and severity. Wounds due to firearms can be deep and with substantial tissue destruction. Dismemberment due to trauma requires immediate intervention to stop blood loss from the severed limb.
Liquid bandage formulations are available to the Over-the-Counter (OTC) consumer market. Liquid bandage preparations are often used for covering and protecting minor lacerations and abrasions, friction blisters and paper cuts. When applied to the skin, the solution evaporates to form a protective film over the application area and to promote healing. The polymerized film covering creates a moist wound healing environment to increase wound healing compared with conventional dressings. Most liquid bandage preparations claim to stop minor bleeding, create a protective seal over the wound, and keep out water, dirt and germs. These preparations generally act as a mechanical barrier to common microbial organisms and other forms of contamination. Liquid bandage products are available from numerous commercial sources and include New Skin Liquid Bandage, Nexcare Bandages Spray Liquid Bandage, Liquid Bandage by J&J, Skin Shield Liquid Bandage Curad Spray Bandage. Powder-based hemostats are also widely available OTC in products such as QuikClot (Z-Medica), Urgent QR and Nosebleed QR (BIOLIFE), TraumaDEX and Bleed-X (Medafor), Celox (MEDTRADE Biopolymers), ActCel (ActSys Medical), and Quick Relief.
Publication WO 96/17633 describes tissue sealants including a fibrin bandage. In the method used for generating the bandage described in the WO publication, the active components are lyophilized in separate layers which are supported by an occlusive backing. Therefore, the active components are not homogeneously mixed throughout the bandage.
EP 1073485 (Zymogenetics) describes fully recombinant tissue sealant compositions, but makes no reference to dry powder forms.